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. 2022 Aug;150(2):415-424.
doi: 10.1016/j.jaci.2022.04.007. Epub 2022 Apr 20.

Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease

Kathleen M Buchheit  1 , Aaqib Sohail  1 , Jonathan Hacker  2 , Rie Maurer  3 , Deborah Gakpo  2 , Jillian C Bensko  2 , Faith Taliaferro  4 , Jose Ordovas-Montanes  5 , Tanya M Laidlaw  6
Affiliations

Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease

Kathleen M Buchheit et al. J Allergy Clin Immunol. 2022 Aug.

Abstract

Background: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated.

Objective: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab.

Methods: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing.

Results: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia.

Conclusion: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.

Keywords: AERD; Aspirin-exacerbated respiratory disease; IL-13; IL-4; IL-4Rα; anosmia; dupilumab; leukotriene E(4); nasal polyp; prostaglandin E(2).

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Conflict of interest statement

Conflict of Interest: T Laidlaw has served on scientific advisory boards for GlaxoSmithKline, AstraZeneca, Sanofi-Genzyme, and Regeneron. K Buchheit has served on scientific advisory boards for AstraZeneca, Sanofi-Genzyme, Regeneron, and GlaxoSmithKline. J Bensko has served on scientific advisory boards for GlaxoSmithKline. J Ordovas-Montanes. reports compensation for consulting services with Cellarity and Hovione.

Figures

Figure 1:
Figure 1:. Dupilumab-induced changes in clinical upper respiratory outcomes.
Smell identification level as measured by UPSIT is shown as raw scores (A) or as summarized levels of anosmia, hyposmia, or normosmia (B) at the pre-dupilumab baseline, and after 1 and 3 months of treatment with dupilumab. SNOT-22 scores (C), peak nasal inspiratory flow (PNIF) (D), and otoscopically scored bilateral nasal polyp scores (E) are shown for the same timepoints. Data in A, C-E are shown as Tukey’s box-and-whisker plots, N = 22 participants.
Figure 2:
Figure 2:. Dupilumab-induced changes in pulmonary outcomes.
Pulmonary function and asthma control as measured by liters of FEV1 (A), FEV1 % predicted (B), liters of FVC (C), and ACQ-6 (D) are shown at the pre-dupilumab baseline, and after 1 and 3 months of treatment with dupilumab. Data are shown as Tukey’s box-and-whisker plots, N = 22 participants.
Figure 3:
Figure 3:. Dupilumab-induced changes in nasal and urinary eicosanoids.
Urinary levels of LTE4, tetranor-PGDM, and PGE-M (A-C), and nasal fluid levels of LTE4, DHKPGD2, and PGE2, (D-E) are shown at the pre-dupilumab baseline, and after 1 and 3 months of treatment with dupilumab. Data are shown as Tukey’s box-and-whisker plots, analysis with Wilcoxon signed-rank test, N = 22 participants.
Figure 4:
Figure 4:. Relationship between nasal PGE2 and sense of smell.
Nasal fluid PGE2 levels of patients who were anosmic (could identify <19 items on the UPSIT) or hyposmic/normosmic (could identify ≥19 items on the UPSIT) at baseline are compared (A). Correlations between baseline nasal PGE2 levels and baseline UPSIT score (B) and between the dupilumab-induced change from baseline to month 1 in nasal PGE2 and UPSIT score (C) are shown with Spearman correlation coefficients.
Figure 5:
Figure 5:. Dupilumab-induced decrease in nasal albumin and ECP.
Nasal fluid levels of albumin (A) and eosinophilic cationic protein (ECP) (B) are shown at the pre-dupilumab baseline, and after 1 and 3 months of treatment with dupilumab. Data are shown as Tukey’s box-and-whisker plots.
Figure 6:
Figure 6:. Dupilumab-induced decrease in IgE.
Serum IgE (A) and nasal fluid IgE (B) levels are shown at the pre-dupilumab baseline, and after 1 and 3 months of treatment with dupilumab. Data are shown as Tukey’s box-and-whisker plots.
Figure 7:
Figure 7:. Dupilumab-induced differntial gene expression and gene enrichment analyses.
Volcano plots showing dupilumab-induced differential gene expression at month 1 compared to baseline (A) and month 3 compared to baseline (B). Gene ontogeny analysis reveals upregulation and downregulation of specific pathways by dupilumab treatment after 1 and 3 months of treatment (C).
See this image and copyright information in PMC

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